Emerging evidence suggests that an epigenetic misregulation of the genome, including brain region-specific altered DNA promoter methylation, is associated with the neuropathological manifestations of alcohol abuse and dependence. DNA (cytosine) methylation generally has been regarded as a highly stable epigenetic mark that ensures and maintains neuronal phenotype identity. However, the epigentic DNA marking is highly dynamic and requires the action of a family of DNA-methyltransferases (DNMT) and an active DNA-demethylation pathway (base excision repair [BER] pathway) that includes 5methyl cytosine (5MC) hydroxylation by a ten-eleven-translocation (TET) and deamination by an apolipoprotein B mRNA editing enzyme (Apobec). Our preliminary studies in bipolar (BP) disorder and major depressed (MD) patients who are also chronic alcoholics show decreased DNMT and a marked increase of TET-1 expression in the prefrontal cortex compared to controls. In BP and MD patients with comorbid alcoholism, there is also increased 5-hydroxyMC at GAD67 and BDNF promoters. The objective of our study is to investigate the expression and promoter binding of components of the DNA-methylation and DNA-demethylation network in corticolimbic structures of chronic uncomplicated alcoholics (no developmental disorders, no other psychiatric and neurological disorders) who consumed greater than 80 g of ethanol/day, obtained from the New South Wales Tissue Resource Center (see attached letter). Our working hypothesis is that DNA-methylation/demethylation dynamics may be involved in behavioral aspects of alcohol exposure in part through epigenetically mediated disruption of the balance between glutamatergic /GABAergic transmission and synaptic plasticity at corticolimbic circuit neurons. Testing this hypothesis in a cohort of uncomplicated chronic alcoholic subjects will reveal novel alcohol sensitive targets with obvious important therapeutic and public health implications, protein networks in human brain has obvious therapeutic and public health implications.